Fibroblast growth factor receptor inhibitors ameliorate metabolic dysfunction-associated steatohepatitis by modulating the glycine-glutathione-gut microbiota axis

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by hepatic steatosis, inflammation, and fibrosis. Dysregulation of fibroblast growth factor receptor (FGFR) signaling is closely associated with various liver diseases, but its role in hepatic metabolism remains unclear. In this study, we developed a small-molecule FGFR inhibitor, CP0813, and evaluated its therapeutic potential in three diet-induced MASH mouse models. Using multi-omics analyses (metabolomics, transcriptomics, and microbiomics), we explored the genetic and metabolic features of MASH as well as the mechanisms of action of CP0813. The results showed that CP0813 inhibited all four FGFR subtypes by over 90 % and significantly improved hepatic steatosis, inflammation, and fibrosis in MASH mice. It exerted antifibrotic effects by inhibiting the FGFR and Transforming growth factor-β (TGF-β)/Smad signaling pathways. Multi-omics analysis further revealed that CP0813 improved MASH by regulating glycine metabolism, glutathione synthesis, and the gut microbiota, with significant interconnections at the genetic, metabolite, and microbial levels. In conclusion, this study not only elucidated the critical role of the FGFR signaling pathway in the pathogenesis of MASH but also provided strong scientific evidence and a potential drug candidate for the development of novel therapeutic strategies for MASH, holding important implications for clinical translation.